Fig. 3

Signaling pathways which CD44 regulates. CD44v6 can enroll ERM proteins which can interact with VEGFR, contributing angiogenesis. CD44 activates AKT to promote the phosphorylation and nuclear translocation of MDM2, which blocks p53 genomic surveillance response. Subsequently, damaged hepatocytes escape from p53-mediated death, and carcinogen-induced mutations are maintained and transferred from parental cells to daughter cells, ultimately contributing to tumorigenesis. The combination of HA and CD44v6 promotes the phosphorylation of intracellular domain of CD44v6, which then activates Ras and FAK via Src and activates MAPK/ERK signaling. CD44v6 in combination with HA also promotes the PI3K/Akt signaling pathway and increases apoptosis. The intracellular tail of CD44v6 increases MMP2 and MMP9, which degrades ECM and promotes maturation of TGFβ. After binding to its receptor, TGFβ stabilizes β-catenin intracellularly via Smad3 together with activated Akt. Nucleus β-catenin stabilization enhances the expression of EMT-related genes and the gene encoding CD44v6. CD44v6 up-regulation enhances the expression of HA synthase genes, which promotes HA production. CD44 contributes to the dissociation of E-cadherin and β-catenin through suppression of E-cadherin, and then β-catenin translocates to nucleus